The STAT5 proteins are involved in key cell functions including proliferation, differentiation and survival. Persistent STAT5 activation occurs in malignant cells of both hematopoietic and nonhematopoietic origin. There are two separate STAT5 proteins, STAT5a and STAT5b that are encoded by two closely related genes. Although the proteins have 94% sequence identity, gene knockout mouse models showed that STAT5a and STAT5b have certain distinct, non-overlapping functions. The exact role of STAT5a as opposed to STAT5b in malignant cell transformation is much less well understood.
Epigenetic gene silencing performs an important function in carcinogenesis by inhibiting expression of many tumor-suppressor genes. Methylation of the CpG islands in the gene promoter region is the key component of the process. CpG methylation is mediated by members of the DNA methyltransferase (DNMT) family that can be inactivated by small-molecule inhibitors such as 5′-aza-2′-deoxy-cytidine (5′-aza). Another class of proteins, designated MBD, also plays a key part in epigenetic gene silencing by binding to the methylated CpG sites and interfering with binding of transcription activators. One member of this group, MeCP2, is capable of binding to single CpG sites.
Normally, ALK tyrosine kinase expression seems confined to neural cells. Its ectopic expression in a subset of T-cell lymphomas (ALK+ TCL) and other malignancies typically results from chromosomal translocations involving the ALK gene and various partners, for example the nucleophosmin (NPM1) or echinoderm microtubule-associated protein-like 4 (EML4) gene. The NPM-ALK protein contains the NPM oligomerization motif and the ALK catalytic domain, is constitutively activated through autophosphorylation, and mediates malignant cell transformation in vitro and in vivo by activating downstream effectors including STAT3.